Chemotherapy with cytotoxic drugs is successful when these drugs either preferentially kill cancer cells, or preferentially accumulate in tumors compared to other tissues. Yet, neither case holds true for the 52,000 Americans diagnosed last year with head and neck squamous cell carcinoma (HNSCC). HNSCC originates in the mucosal tissues of the head and neck, but it rapidly metastases throughout the cervical lymphatics, which presents a daunting clinical challenge. The cytotoxic anti-cancer drugs used to treat HNSCC have very poor penetration into these lymphatics, and left undertreated the HNSCC will relapse in up to 70% of patients. The primary objective of this work is the synthetic development and biological evaluation of a new polymeric biomaterial for chemotherapy of the head and neck tissues. This innovative approach will perform better than any existing therapy because chemotherapy is delivered directly into prone tissues so delicate organs are not damaged, and this is accomplished with the first nanoparticle system specifically engineered for exceptional drug delivery into cancerous lymph nodes and tissues after peri-tumoral injection. The new biomaterial, star nanoconjugates, can be targeted to HNSCC tumors without expensive and less robust homing ligands, such as antibodies or aptamers. The first aim is to synthesize a library of star nanoconjugates of chemotherapeutics, including both standard-of-care drugs, new nitric oxide-based drugs that synergize with existing drugs, and the first photodynamic nitric oxide treatment. The star nanoconjugates are synthetic sugar-based star polymers that collapse into compact nanoscopic carriers when conjugated to common anticancer drugs. The physiochemical properties of the resulting nanoconjugates can be synthetically tailored for excellent lymphatic uptake and retention, tumor penetration, and sustained drug release within the lymphatics surrounding tumors. In the second aim, fluorescent imaging and radiological tracking of the nanoconjugates and drugs in rodents after locoregional injection will demonstrate the superior delivery of chemotherapy into HNSCC tumors. Subsequently, PET/CT imaging of canines with spontaneous oral squamous cell carcinoma (SCC) will verify performance of this platform in a more man-like model. Third, the efficacy and safety of HNSCC treatment with star nanoconjugates will be compared to conventional chemotherapy in rodent xenografts of HNSCC. Fourth, a Phase I canine trial in patients with spontaneous oral SCC cancer will demonstrate efficacy and safety in a large animal model. At the end of this study, there will be proof in a large animal, whose disease closely models human HNSCC, that this treatment is both superior in safety and more efficacious than current chemotherapies. Based on extensive preliminary results in rodents and canines, this platform is expected to significantly impact human health by reducing the need for extensive surgery and radiotherapy, treatments that cause permanent disfigurement and reduce quality-of-life, and provide a much safer alternative to systemic chemotherapy that can be administered to even severely weaken and advanced patients.